EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay

Abstract

In recent years, several genes have been implicated in the variable disease presentation of global developmental delay (GDD) and intellectual disability (ID). The endoplasmic reticulum membrane protein complex (EMC) family is known to be involved in GDD and ID. Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders. EMC10 is a bone marrow-derived angiogenic growth factor that plays an important role in infarct vascularization and promoting tissue repair. However, this gene has not been previously associated with human disease. Herein, we describe a Saudi family with two individuals segregating a recessive neurodevelopmental disorder. Both of the affected individuals showed mild ID, speech delay, and GDD. Wholeexome sequencing (WES) and Sanger sequencing were performed to identify candidate genes. Further, to elucidate the functional effects of the variant, quantitative real-time PCR (RT-qPCR)-based expression analysis was performed. WES revealed a homozygous splice acceptor site variant (c.679-1G>A) in EMC10 (chromosome 19q13.33) that segregated perfectly within the family. RT-qPCR

Identification of the TTC26 Splice Variant in a Novel Complex Ciliopathy Syndrome with Biliary, Renal, Neurological, and Skeletal Manifestations

“…All reactions were performed in triplicate and repeated independently. Expression-Suite software version 1.1 (Applied Biosystems) was used for analysis [Asiri et al, 2020;Umair et al, 2020].…”

Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish

“…After WES, as depicted by the family pedigree, variant filtration was performed based on the autosomal recessive pattern of inheritance. Screening of rare disease-causing homozygous and compound heterozygous variants was preferred (Umair et al, 2020). Initial screening was conducted in the genes classified in OMIM and HGMD.…”

The endoplasmic reticulum membrane protein complex (EMC) negatively regulates intestinal homeostasis through the Hippo signaling pathway

“…EMC has been proven to perform multiple functions in organisms: it mediates the insertion of the transmembrane domain (TMD) into the lipid bilayer and can act as a chaperone to participate in the folding of other types of membrane proteins in the ER (Shurtleff et al, 2018;Tang et al, 2017;Volkmar and Christianson, 2020). The lack of EMC will affect the physiological functions of organisms, such as ER stress, lipid homeostasis, tissue homeostasis, and autophagy (Chitwood et al, 2018;Huang et al, 2021;Li et al, 2013;Umair et al, 2020;Volkmar et al, 2019;Yu et al, 2021;Zhu et al, 2020). In addition, EMC10 governs male fertility via maintaining sperm ion balance in mice (Zhou et al, 2018), and EMC deficiency in Drosophila induces defective phototransduction and photoreceptor degeneration (Satoh et al, 2015;Xiong et al, 2020).…”